Phase 1/2 study of weekly carfilzomib, cyclophosphamide, dexamethasone in newly diagnosed transplant-ineligible myeloma

Bringhen, Sara; D’Agostino, Mattia; Paoli, Lorenzo De; Montefusco, Vittorio; Liberati, Anna Marina; Galieni, Piero; Grammatico, Sara; Muccio, Vittorio Emanuele; Esma, Fabrizio; Angelis, Carmine De; Musto, Pellegrino; Ballanti, Stelvio; Offidani, Massimo; Petrucci, Maria Teresa; Gaïdano, Gianluca; Corradini, Paolo; Palumbo, Antônio; Sonneveld, Pieter; Boccadoro, Mario

doi:10.1038/leu.2017.327

Cited by 27 publications

(31 citation statements)

References 36 publications

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“…These data supported the recent approval of once‐weekly carfilzomib (70 mg/m 2 ) with dexamethasone for the treatment of patients with RRMM . Other phase 1 and phase 1/2 studies have explored once‐weekly carfilzomib across the MM disease continuum, and have thus far demonstrated promising efficacy and tolerability for this schedule . These studies have explored once‐weekly carfilzomib in combination with cyclophosphamide‐dexamethasone, pomalidomide‐dexamethasone, lenalidomide‐dexamethasone, daratumumab‐dexamethasone, and daratumumab‐lenalidomide‐dexamethasone at carfilzomib doses ranging from 27 to 70 mg/m 2 .…”

Section: Discussionmentioning

confidence: 58%

Weekly carfilzomib, lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: A phase 1b study

et al. 2019

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Twice‐weekly carfilzomib (27 mg/m2) with lenalidomide‐dexamethasone (KRd) is a standard‐of‐care in relapsed or refractory multiple myeloma (RRMM). This phase 1b study evaluated KRd with once‐weekly carfilzomib in RRMM. Patients received carfilzomib (30‐minute infusion; 56 or 70mg/m2) on days 1, 8, and 15; lenalidomide 25 mg on days 1‐21; and dexamethasone 40 mg on days 1, 8, 15, and 22 (day 22 omitted for cycles 9+) of 28‐day cycles. Primary objective was safety/tolerability; efficacy was a secondary objective. Fifty‐six RRMM patients enrolled: 22 during dose evaluation (56‐mg/m2, n = 10; 70‐mg/m2, n = 12) and 34 during dose expansion (all initiated dosing at 70 mg/m2). After 2 fatal adverse events (AEs) during 70‐mg/m2 dose expansion, dosage reduction to 56 mg/m2 was permitted. Results are presented for carfilzomib 56‐mg/m2 (n = 10) and 70‐mg/m2 groups (dose evaluation/expansion; n = 46). Median carfilzomib dose was 53.2 mg/m2 (56‐mg/m2 group) and 62.4 mg/m2 (70‐mg/m2 group). Grade ≥3 AE rates were 70.0% (56 mg/m2) and 69.6% (70 mg/m2). Overall response rates were 90.0% (56 mg/m2) and 89.1% (70 mg/m2); ≥very good partial response rates were 50.0% (56 mg/m2) and 73.9% (70 mg/m2). Once‐weekly KRd was active with acceptable toxicity in RRMM, supporting further evaluation of this regimen.

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Section: Discussionmentioning

confidence: 58%

Weekly carfilzomib, lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: A phase 1b study

et al. 2019

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“…In addition, this schedule may not be possible for patients with body surface area (BSA) > 1.7 m 2 given that the maximum carfilzomib dose reimbursed on the Australian Pharmaceutical Benefits Scheme is capped at 120 mg. If weekly dosing of carfilzomib is used, it is not unreasonable to consider adding cyclophosphamide (KCd) as this weekly schedule has been shown to be effective and safe in the upfront treatment setting (IV) …”

Section: Myelomamentioning

confidence: 99%

Australian and New Zealand consensus statement on the management of lymphoma, chronic lymphocytic leukaemia and myeloma during the COVID‐19 pandemic

Ciaccio

McCaughan

Trotman

et al. 2020

Internal Medicine Journal

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“…In the phase 3B community-based UPFRONT study, fixedduration single-agent bortezomib maintenance following bortezomib-based induction improved response depth in approximately 16% of patients, with limited new-onset toxicity 78 . A phase 1/2 study has shown the feasibility and activity of carfilzomib maintenance following weekly carfilzomib-cyclophosphamide-dexamethasone induction, with response improvements again being reported 79 .…”

Section: Maintenance Therapy Post-induction In the Nontransplant Settingmentioning

confidence: 99%

Developments in continuous therapy and maintenance treatment approaches for patients with newly diagnosed multiple myeloma

et al. 2020

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The evolving paradigm of continuous therapy and maintenance treatment approaches in multiple myeloma (MM) offers prolonged disease control and improved outcomes compared to traditional fixed-duration approaches. Potential benefits of long-term strategies include sustained control of disease symptoms, as well as continued cytoreduction and clonal control, leading to unmeasurable residual disease and the possibility of transforming MM into a chronic or functionally curable condition. "Continuous therapy" commonly refers to administering a doublet or triplet regimen until disease progression, whereas maintenance approaches typically involve single-agent or doublet treatment following more intensive prior therapy with autologous stem cell transplant (ASCT) or doublet, triplet, or even quadruplet induction therapy. However, the requirements for agents and regimens within these contexts are similar: treatments must be tolerable for a prolonged period of time, should not be associated with cumulative or chronic toxicity, should not adversely affect patients' quality of life, should ideally be convenient with a minimal treatment burden for patients, and should not impact the feasibility or efficacy of subsequent treatment at relapse. Multiple agents have been and are being investigated as long-term options in the treatment of newly diagnosed MM (NDMM), including the immunomodulatory drugs lenalidomide and thalidomide, the proteasome inhibitors bortezomib, carfilzomib, and ixazomib, and the monoclonal antibodies daratumumab, elotuzumab, and isatuximab. Here we review the latest results with long-term therapy approaches in three different settings in NDMM: (1) maintenance treatment post ASCT; (2) continuous frontline therapy in nontransplant patients; (3) maintenance treatment post-frontline therapy in the nontransplant setting. We also discuss evidence from key phase 3 trials. Our review demonstrates how the paradigm of long-term treatment is increasingly well-established across NDMM treatment settings, potentially resulting in further improvements in patient outcomes, and highlights key clinical issues that will need to be addressed in order to provide optimal benefit.

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Phase 1/2 study of weekly carfilzomib, cyclophosphamide, dexamethasone in newly diagnosed transplant-ineligible myeloma

Cited by 27 publications

References 36 publications

Weekly carfilzomib, lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: A phase 1b study

Weekly carfilzomib, lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: A phase 1b study

Australian and New Zealand consensus statement on the management of lymphoma, chronic lymphocytic leukaemia and myeloma during the COVID‐19 pandemic

Developments in continuous therapy and maintenance treatment approaches for patients with newly diagnosed multiple myeloma

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